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Most research into nanomedicine, the application of nanoscale materials and processes to medical problems, has focused on cancer. Now researchers are starting to see opportunities for these approaches in Alzheimer’s disease (AD). With its Seventh Framework Programme (FP7) for research, the European Union (EU) has boosted funding of nanomedicine, especially projects involving large cross-European collaborations, to help move the technology forward (see Part 1). One project that has benefited is Nanoparticles for Therapy and Diagnosis of Alzheimer's Disease, aka NAD. With a budget of €14.37 million (US$20.8 million), this project aims to find nanometer-sized particles that can slow the progression of AD.

One of the challenges for applying nanomedicine approaches to AD is that the drugs or imaging agents have to be transported across the blood-brain barrier to the brain—no easy feat. To solve this problem, Massimo Masserini of the Universitá Degli Studi di Milano-Bicocca in Italy, who heads the NAD project, said, “It was important to put together a big task force.” Masserini assembled a group of 19 research groups from 13 European countries spanning different areas of expertise. “NAD is a very large consortium. They have experts in the chemistry of ligands and nanoparticles, biochemists, pharmacologists, people in charge of commercializing medical products, and clinicians,” said Terry Allen, a pharmacologist who works on drug-delivery methods at the University of Alberta, Canada, and is a member of the international advisory board for NAD. “I don’t know of another large group taking this nanotechnology-based approach to AD.”

Since the project’s launch in October 2008, NAD researchers have designed a number of natural and synthetic nanoparticles that are eventually degraded in the body, reducing concerns about toxicity. Julien Nicolas, a polymer chemist in Patrick Courvreur’s group at the Université Paris-Sud in Châtenay-Malabry, France, synthesized biodegradable polymeric nanoparticles covered by chains of polyethylene glycol (PEG), which helps hide the nanoparticles from the immune system. Other groups in NAD have developed solid lipid nanoparticles and liposomes. As a second step, these nanoparticles have been linked to an array of ligands that interact with amyloid-β (Aβ), such as acidic phospholipids, anti-Aβ antibodies, and a derivative of the molecule curcumin, which is purported to break up Aβ aggregates (see ARF related news story on Yang et al., 2005). Since last December, the NAD group has published several papers showing that various combinations of ligands and nanoparticles bind Aβ in blood and brain tissue samples (Brambilla et al., 2010; Canovi et al., 2011; Mourtas et al., 2011; Gobbi et al., 2010). They then reported that these agents, when applied to neurons in culture, can reduce Aβ toxicity, said Masserini (Bereczki et al., 2011).

The scientists are now planning to deploy their arsenal of compounds in two ways: One is to couple them with other ligands that will get them across the blood-brain barrier into the brain, where they can target amyloid deposits directly; the other is to try to clear Aβ from the blood and hope it will reduce Aβ in the brain through a sink effect (see ARF related news story on Yamada et al., 2009). “There is a theory that Aβ in the blood and brain are in equilibrium,” said Nicolas. “Some people believe that removal of Aβ from blood will displace this equilibrium and cause Aβ to clear the brain.” Researchers have had some success with this approach in mouse models (see ARF related news story on DeMattos et al., 2001) and an anti- Aβ antibody postulated to work in this way has been advanced to Phase 3 trials (seesolanezumab and ARF related news story). To test this approach, “we have made some nanoparticles in such a way that they will not have a long circulating time,” said Sophia Antimisiaris of the University of Patras in Greece. “But they stay in the circulation long enough that they can bind Aβ and extract it from the blood.” Taking this strategy would bypass the problem of having to cross the blood-brain barrier, but Antimisiaris acknowledged that it is a longshot, as the peripheral sink hypothesis remains controversial. Even so, the group has started to test their initial non-barrier-crossing compounds in animal models of AD. “We are really at the beginning of the story,” said Gianluigi Forloni of the Mario Negri Institute in Milan, Italy, whose group is carrying out the animal work.

At the same time, the NAD group is designing nanoparticles that will access the brain by incorporating ligands such as the molecule transferrin, which binds to a receptor on the endothelial cells of the blood-brain barrier (Markoutsa et al., 2011) and is already being tested for ferrying antibodies into the brain to block Aβ production (see ARF related news story). NAD researchers are also adding to the nanoparticles PET and MRI contrast agents for Aβ so that they could monitor the progression of disease at the same time they deliver therapy (Skouras et al. 2011). Masserini refers to this approach as theranostics, variously spelled theragnostics (e.g., Zetterberg et al., 2011).

The NAD project is about halfway through its funding cycle. In the next two and a half years, Masserini said the consortium should complete experiments testing several compounds in transgenic mice. “It is a high-risk but potentially high-reward project if it works out,” said Cristina Gabellieri of the EU’s directorate general for research and innovation.

Not Just Therapy
Although new therapies against AD are sorely needed, just as important are methods to diagnose the disease at an earlier stage than is currently possible, as the failure of several candidate drugs at Phase 3 trials suggest that treatment may have started when it was already too late (see ARF related news story). “The real potential for nanotechnology may lie in detecting disease at an early stage. If we can do that, we can then apply therapies either delivered by nanoparticles or in a traditional fashion,” said Tara Spires-Jones at Massachusetts General Hospital. “Right now we have a wonderful agent, PIB, that crosses the blood-brain barrier and binds to Aβ plaques, but we have no way of imaging oligomeric or soluble Aβ. We also have no markers for tau that cross the blood-brain barrier,” she added (see ARF related news story). Such agents might allow the detection of disease at earlier stages than imaging plaques. Although NAD is not investigating such compounds, this is something that Spires’ group and others are doing, but that work has not yet been published.

Besides delivering imaging agents to the brain, nanoscale approaches can help detect AD biomarkers in the CSF or blood (see ARF related news story on Haes et al. 2005). The EU FP7 has given a separate €9 million grant to a large consortium called NADINE (Nanosystems for the Early Diagnosis of Neurodegenerative Diseases) that aims to develop a nanofluidics-based system for measuring AD biomarkers in blood. “Nanotechnology opens the door for lower-cost tests and developing devices that can detect small amounts of the biomarker,” said Susana Aznar Kleijn at the Technical University of Denmark in Kongens Lyngby, north of Copenhagen, the project’s coordinating center. The consortium is currently conducting experiments to establish the best biomarkers and sensor approaches.

A smaller FP7 project also developing a blood test for AD is Nanognostic. With a budget of €5.3 million (of which €4 million comes from the FP7), this collaborative project will attempt to develop a diagnostic for AD based on five proteins chosen from a panel of 18 shown to be predictive of AD (see ARF related news story on Ray et al., 2007). Their strategy uses fluorescence resonance energy transfer (FRET) from luminescent lanthanide complexes to semiconductor quantum dots, both of which are linked with antibodies and aptamers that recognize the five proteins. “The system that we are developing can measure small amounts of proteins in blood sensitively and very quickly. You can measure multiple proteins simultaneously in one sample,” said Niko Hildebrandt at the Université Paris-Sud in Orsay, France. In a proof-of-principle paper, the scientists showed that the technique can work with proteins unrelated to AD (Geissler et al., 2010); they are now applying the method to samples from AD patients.

“The EU has been very quick in calling for proposals for new promising technology that they want to grow, and in having researchers with existing expertise work together,” said Pieter Jelle Visser at Maastricht University in The Netherlands and a member of the European Alzheimer's Disease Consortium and the EU’s Joint Programming Initiative on Neurodegeneration. “I think it’s a good thing.”—Laura Bonetta